Pregabalin, a compound of Formula I, is the international commonly accepted name for (S)-(+)-3-aminomethyl-5-methyl-1-hexanoic acid and has an empirical formula of C8H17NO2. Pregabalin is also known as (S)-(+)-3-(2-methylpropyl)-4-aminobutanoic acid or (S)-(+)-3-isobutyl-GABA. Pregabalin is a commercially marketed pharmaceutically active substance known to be useful as therapeutic agent for treatment of pain, convulsions, general anxiety related disorders and epilectic seizures.

Pregabalin and its pharmaceutically acceptable salts are described in U.S. Pat. No. 6,197,819 (“the '819 patent”), along with two different synthetic processes for their preparation. However, these routes involve expensive and/or difficult to handle substances such as (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone, n-butyllithium, and “azide” intermediates. The '819 patent is incorporated herein by reference.
Several patents and published patent applications (e.g, U.S. Pat. No. 5,616,793 (“the '793 patent”) and International Publication Nos. WO 2006/122258 (“the '258 publication”), WO 2006/122255 (“the '255 publication”), and WO 2006/121557 (“the 557 publication”)) disclose a more convenient preparation of pregabalin by means of a Hofmann rearrangement of (R)-(−)-3-(carbamoylmethyl)-5-methylhexanoic acid, a compound of Formula II, in the presence of bromine and an alkali hydroxide as depicted in Scheme 1.
The '793 patent and the '258, '255, and '557 publications are incorporated herein by reference.

However, this synthetic method is not desirable for industrial implementation, since it requires the use of bromine, which is very toxic and corrosive. Moreover, this process involves the formation of undesired by-products. In this regard, it is well-known that the presence of impurities may adversely affect the safety and shelf life of pharmaceutical formulations.
Regarding the synthetic process described in Scheme 1 (i.e., the preparation of pregabalin via a Hofmann rearrangement reaction of a compound of Formula II), Hoekstra et al. in Organic Process Research & Development 1997, 1, 26-38, report that the use of sodium hypochlorite as an alternative to bromine gives poor conversions.
In view of the foregoing, there is a need to provide improved processes for preparing pregabalin which are suitable for industrial implementation, which avoid the use of bromine and which produce pregabalin substantially free of impurities.